Gastroretentive drug formulation and delivery systems and their method of preparation using functionalized calcium carbonate

ABSTRACT

An instantly floating gastroretentive drug formulation comprising at least one functionalized natural and/or synthetic calcium carbonate-comprising mineral and at least one pharmaceutically active ingredient and at least one formulating aid wherein said functionalized natural or synthetic calcium carbonate is a reaction product of natural or synthetic calcium carbonate with carbon dioxide and one or more acids, wherein the carbon dioxide is formed in situ by the acid treatment and/or is supplied from an external source.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. application Ser. No. 14/429,492, filed Mar.19, 2015, which is a U.S. National Phase of PCT Application No.PCT/EP2013/071140, filed Oct. 10, 2013, which claims priority toEuropean Application No. EP 12188419.1, filed Oct. 12, 2012 and U.S.Provisional Application No. 61/713,691, filed Oct. 15, 2012, thecontents of which are hereby incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to gastroretentive drug formulations anddelivery systems using functionalized calcium carbonate and their methodof preparation. The gastroretentive drug delivery system is instantlyfloating and can be in the form of a tablet, mini-tablet, granules,capsules or pellet. The gastroretentive drug delivery system is intendedto remain in the stomach for a prolonged and predictable time deliveringan active ingredient or inactive precursor. Instant flotationhereinafter implies zero lag-time before actual flotation takes place.

BACKGROUND OF THE INVENTION

In comparison to conventional dosage forms, gastroretentive drugdelivery systems (GRDDS) are designed to remain in the stomach for aprolonged and predictable period of time. Consequently, gastricresidence time of drug substances is extended and bioavailabilityimproved. GRDDS are beneficial for a number of drugs, like drugsubstances whose site of action is locally in the stomach and drugswhich exhibit a narrow absorption window in the stomach or in the upperpart of the small intestine. Moreover, drugs which are degraded in theintestinal or colonic environment, as well as drug substances which arepoorly soluble at alkaline pH-values are candidates profiting fromGRDDS.

Various mechanisms have been proposed to achieve gastric retention andavoid unpredictable gastric emptying of dosage forms. These approachesinclude: co-administration of drugs or pharmaceutical excipientsinfluencing gastric motility pattern and thereby delaying gastricemptying process, magnetic systems, mucoadhesive systems,size-increasing systems due to swelling or unfolding, density-controlledsystems that either float on gastric contents or sediment, andcombination systems.

Pawar et al. (Gastroretentive dosage forms: A review with specialemphasis on floating drug delivery systems. Drug Delivery. 2011February; 18(2):97-110) considered floating drug delivery systems (FDDS)as an easy and logical approach regarding formulation and technicalaspects for the development of GRDDS. FDDS are low-density systems witha density less than density of gastric fluids (˜1.004 g/cm³). Therefore,dosage forms float on gastric contents and are retained in the stomachwhile releasing drug.

Since the idea of floating dosage forms was introduced by Davis in 1968(U.S. Pat. No. 3,418,999), many research groups invented differentstrategies for preparation of FDDS. Floatation is achieved byincorporation of low-density materials, by swelling or by gas generationand entrapment. Due to the fact that excipients with density less thanunity provide immediate floating to the delivery device, their use ishighly favored for formulation development.

U.S. Pat. No. 3,976,764 discloses an instantly floating tablet, having ahollow sphere based on gelatin coated with several under-coatings,wherein an therapeutically active ingredient is comprised in one of theunder-coatings.

DE 35 27 852 A1 discloses a pharmaceutical formulation with a specificdensity below 1, wherein a substance forming a gel in water is mixedwith a pharmaceutically active ingredient and a fat/oil which is solidat room temperature. The gel forming substance being a cellulose-,dextran- or starch derivative.

EP 0 338 861 A2, refers to an antacid compositions with prolongedgastric residence time.

The antacid such as Hydrotalcite or Amalgate forming a solid core whichis surrounded by a solid external phase containing a hydrophobicsubstance e.g. an ester of glycerol with palmitic or stearic acid,hydroxylated polyalkene and a non-ionic emulsifier.

EP 0 717 988 A1, refers to a swollen molding which is an expandedstructure having a mesh-like cross-section and an apparent density ofless than 1, which structure is predominantly an acid-resistant polymercompound and additionally containing at least an auxiliary blowing agentand a drug substance. Because of its mesh-like structure incross-section, the swollen molding of the invention has a multiplicityof microfine internal pores which are continuous or discontinuous. Saidacid-resistant polymer compound are chosen, e.g. fromhydroxpropymethylcellulose acetate succinate or phthalate.

U.S. Pat. No. 4,451,260 refers to a multilayered structure comprising apharmaceutical active ingredient wherein air is entrapped in themultilayered structure, thus promoting flotation.

U.S. Pat. No. 4,814,179 refers to a floating sustained releasetherapeutic composition. Non-compressed sustained release tabletscomprise a hydrocolloid gelling agent, a therapeutically acceptableinert oil, the selected therapeutic agent and water.

The presence of pharmaceutically inert fatty materials having a specificgravity of less than one decrease the hydrophilicity and increase thebuoyancy of the dosage form.

Optimal floating tablets have different conflicting characteristics. Onthe one hand, high porosity to float on stomach contents, on the otherhand sufficient hardness to withstand destruction by gastricperistalsis. Further, high porosity having a positive effect on floatinghave at the same time also the disadvantage that when pores are exposedto the gastric fluid, water can enter the pores and fill them up andeven propagate deeper into the pores, particularly when the pores areinterconnected. As a consequence the inherent density will increase andthus decrease the floating capability of the tablet and thus provokingsinking of the tablet at a later stage, and bearing the risk of earlyclearing from the stomach by the know mechanisms such as peristalticmovements. Prior art counter acts this problem by including acids intotheir formulations in the presence of carbonates. The acids release CO₂when in contact with water and by this effervescent mechanism, thetablets keep floating. The drawback however is, that such tablets arefar more quickly dissolved and thus counteract the long residence timein the stomach.

The present invention provides thus for an instantly floatingformulation with gastroretentive properties overcoming the drawbacks ascurrently presented.

The inventors surprisingly found out that particles from the paperindustry can serve as novel pharmaceutical excipient exhibiting a highlyporous meshwork with lamellar surface structure that grips particlesstrongly together. Due to its unique properties, functionalized calciumcarbonate (FCC) is promising for preparation of FDDS. It offers thepossibility to formulate them in to granules, pellets, capsules or tocompact them into tablets or mini-tablets at a relative density of lessthan unity, i.e. less than 1.000 g/cm³.

SUMMARY OF THE INVENTION

The functionalized natural and/or synthetic calcium carbonate (FCC)comprised in the gastroretentive drug delivery system, can be preparedfrom either natural ground calcium carbonate comprising mineral or fromsynthetic calcium carbonate, sometimes also named as precipitatedcalcium carbonate, or from blend of natural and synthetic calciumcarbonates. The present invention also comprises a method of thepreparation of the gastroretentive formulations and delivery systems.

The instantly floating gastroretentive delivery systems can be chosenfrom tablets, mini-tablets, granules or pellets. A further dosage formare capsules. Instantly floating as already indicated by its term floatimmediately on the surface of the gastric fluid after ingestion. Henceno activation of the floating mechanism is needed. The density of theinstantly floating soluble gastroretentive delivery systems is below thedensity of the gastric fluid, which is around 1.004 g/cm³. By this theinitial floating properties as well as the floating properties duringdrug release from the gastroretentive formulation in the gastric fluidis maintained until complete dissolution of the gastroretentiveformulation. These floating properties are achieved by formulating afunctionalized calcium carbonate comprising mineral into an instantlyfloating gastroretentive formulation comprising at least onepharmaceutically active ingredient or inactive precursor, formulationaids and optionally further additives such as film forming substances,flavoring agents, lubricants, effervescent ingredients or colorants.Suitable ingredients being described in the prior art and comprised inthe FDA list of food additives that are generally recognized as safe(GRAS), but not being limited to.

The present invention is further related to a method or process formanufacturing such a instantly floating and gastroretentiveformulations, as well as its dosage forms.

The functionalized calcium carbonate comprising mineral together withthe at least one active ingredient or inactive precursor together withgranulating aids is dry or wet granulated by known methods. The granulescan be dosed directly when being e.g. packaged in sachet or stick packs,or optionally compacted in to tablets, mini-tablets (i.e. tablets withdiameter less than 3 mm) or pellets having a density below the densityof the gastric fluid, e.g. a density below 1.000 g/cm³. A further dosageform can also be in capsules.

DESCRIPTION OF THE INVENTION

The present invention relates to an instantly floating gastroretentivedrug delivery system and to the method of their manufacture usingfunctionalized calcium carbonate. The instantly floating gastroretentivedrug delivery system of the present invention comprises a formulationfor an instantly floating composition.

Said instantly floating gastroretentive formulation comprises at leastone functionalized natural and/or synthetic calcium carbonate comprisingmineral and at least one pharmaceutically active ingredient and at leastone formulating aid, wherein said functionalized natural or syntheticcalcium carbonate is a reaction product of natural or synthetic calciumcarbonate with carbon dioxide and one or more acids, wherein the carbondioxide is formed in situ by the acid treatment and/or is supplied froman external source.

Suitable amount of the functionalized natural or synthetic calciumcarbonate comprising mineral are in the range of 30 wt % to 95 wt %based on the total amount of the composition.

Lower amounts could be used as well, however when made in toformulations the buoyancy might be affected in such way that thefloating ability would be drastically decreased if not completely lost.

The source of natural calcium carbonate for preparing the functionalizedcalcium carbonate (FCC) is selected from the group of marble, calcite,chalk, limestone and dolomite and/or mixtures thereof.

In a particular embodiment the synthetic calcium carbonate for preparingthe functionalized calcium carbonate is precipitated calcium carbonate(PCC) comprising aragonitic, vateritic or calcitic mineralogicalcrystals forms, especially prismatic, rhombohedral or scalenohedral PCCor mixtures thereof.

The process for preparing the functionalized natural and/or syntheticcalcium carbonate (FCC) will now be further described.

In a preferred embodiment, the natural or synthetic calcium carbonate isground prior to the treatment with one or more acids and carbon dioxide.The grinding step can be carried out with any conventional grindingdevice such as grinding mill known to the skilled person.

In a preferred process, the natural or synthetic calcium carbonate,either finely divided, such as grinding, or not, is suspended in water.Preferably the slurry has a content of natural or synthetic calciumcarbonate within the range of 1 wt-% to 80 wt-%, more preferably 3 wt-%to 60 wt-%, and still more preferably from 5 wt-% to 40 wt-%, based onthe weight of the slurry.

In a next step, an acid is added to the aqueous suspension containingthe natural or synthetic calcium carbonate. Preferably, the acid has apK_(a) at 25° C. of 2.5 or less. If the pK_(a) at 25° C. is 0 or less,the acid is preferably selected from sulphuric acid, hydrochloric acid,or mixtures thereof. If the pKa at 25° C. is from 0 to 2.5, the acid orits metal salt is preferably selected from H₂SO₃, HSO₄ ⁻M⁺, H₃PO₄, H₂PO₄⁻M⁺ or mixtures thereof, wherein M⁺ can be Na⁺ and/or K⁺.

In another embodiment, the acid is preferably phosphoric acid incombination with acetic, formic or citric acid or acid salts thereof.

More preferably, the acid is phosphoric acid alone.

The one or more acids can be added to the suspension as a concentratedsolution or a more diluted solution. Preferably, the molar ratio of theH₃O⁺ ion to the natural or synthetic calcium carbonate is from 0.1 to 2.

As an alternative, it is also possible to add the acid to the waterbefore the natural or synthetic calcium carbonate is suspended.

In a next step, the natural or synthetic calcium carbonate is treatedwith carbon dioxide. If a strong acid such as sulphuric acid orhydrochloric acid or a medium-strong acid is used for the acid treatmentof the natural or synthetic calcium carbonate, the carbon dioxide isautomatically formed. Alternatively or additionally, the carbon dioxidecan be supplied from an external source.

Acid treatment and treatment with carbon dioxide can be carried outsimultaneously which is the case when a strong acid is used. It is alsopossible to carry out acid treatment first, e.g. with a medium strongacid having a pK_(a) in the range of 0 to 2.5, followed by treatmentwith carbon dioxide supplied from an external source.

Preferably, the concentration of gaseous carbon dioxide in thesuspension is, in terms of volume, such that the ratio (volume ofsuspension):(volume of gaseous CO₂) is from 1:0.05 to 1:20, even morepreferably 1:0.05 to 1:5.

In a preferred embodiment, the acid treatment step and/or the carbondioxide treatment step are repeated at least once, more preferablyseveral times.

Subsequent to the acid treatment and carbon dioxide treatment, the pH ofthe aqueous suspension, measured at 20° C., naturally reaches a value ofgreater than 6.0, preferably greater than 6.5, more preferably greaterthan 7.0, even more preferably greater than 7.5, thereby preparing thefunctionalized natural or synthetic calcium carbonate as an aqueoussuspension having a pH of greater than 6.0, preferably greater than 6.5,more preferably greater than 7.0, even more preferably greater than 7.5.If the aqueous suspension is allowed to reach equilibrium, the pH isgreater than 7. A pH of greater than 6.0 can be adjusted without theaddition of a base when stirring of the aqueous suspension is continuedfor a sufficient time period, preferably 1 hour to 10 hours, morepreferably 1 to 5 hours.

Alternatively, prior to reaching equilibrium, which occurs at a pHgreater than 7, the pH of the aqueous suspension may be increased to avalue greater than 6 by adding a base subsequent to carbon dioxidetreatment. Any conventional base such as sodium hydroxide or potassiumhydroxide can be used.

Further details about the preparation of the functionalized naturalcalcium carbonate are disclosed in WO 00/39222 and US 2004/0020410 A1,wherein the functionalized natural calcium carbonate is described as afiller for paper manufacture, the content of these references herewithbeing included in the present application.

Yet a different process for the preparation of functionalized naturalcalcium carbonate suitable for the present invention is disclosed in EP2 264 108 of the same applicant, the content of this reference beingherewith included in the present application. Basically, the process forpreparing a functionalized calcium carbonate in an aqueous environmentcomprises the following step:

-   -   a) providing at least one ground natural calcium carbonate        (GNCC);    -   b) providing at least one water-soluble acid;    -   c) providing gaseous CO₂;    -   d) contacting said GNCC of step a) with said acid of step b) and        with said CO₂ of step c);

characterized in that:

-   -   (i) said acid (s) of step b) each having a pKa of greater than        2.5 and less than or equal to 7, when measured at 20° C.,        associated with the ionisation of their first available        hydrogen, and a corresponding anion formed on loss of this first        available hydrogen capable of forming water-soluble calcium        salts;    -   (ii) following contacting said acids(s) with said GNCC, at least        one water-soluble salt, which in the case of a        hydrogen-containing salt has a pKa of greater than 7, when        measured at 20° C., associated with the ionisation of the first        available hydrogen, and the salt anion of which is capable of        forming water-insoluble calcium salts, is additionally provided.

The ground natural calcium carbonate is selected form the groupconsisting of marble, chalk, calcite, limestone and mixtures thereof.Suitable particle sizes of the GNCC can be easily found in the citedreference, as well as the water-soluble acids, e.g. particles withweight median diameter of 0.01 to 10 μm, and acids selected from aceticacids, formic acid, propanoic acid, and mixtures thereof.

The following examples are illustrative for the production of FCC's fromdifferent starting material.

Starting Material: Limestone

A calcium carbonate suspension is prepared by adding water andundispersed limestone (ground under wet conditions in water, optionallyin the presence of a food approved dispersing or grinding aid such asMonopropyleneglycol (MGP)) having a d₅₀ of 3 μm, wherein 33% ofparticles have a diameter of less than 2 μm—in a 20-L stainless steelreactor, such that the aqueous suspension obtained has a solids contentcorresponding to 16 wt % by dry weight relative to the total suspensionweight. The temperature of this suspension is thereafter is brought toand maintained at 70° C.

Under stirring at approximately 1000 rpm such that an essential laminarflow is established phosphoric acid in the form of a 30% solution isadded to the calcium carbonate suspension through a separate funnel overa period of 10 minutes in an amount corresponding to 30% by weight ondry calcium carbonate weight. Following this addition, the suspension isstirred for an additional 5 minutes.

The resulting suspension was allowed to settle overnight, and the FCChad a specific surface area of 36 m²/g, and d₅₀ of 9.3 μm (Malvern) andd₉₈ of 23.5 (Malvern).

Starting Material: Marble

A calcium carbonate suspension is prepared by adding water andundispersed marble (ground under wet conditions in water, optionally inthe presence of a food approved dispersing or grinding aid such asMonopropyleneglycol (MPG)) having a d₅₀ of 3.5 μm, wherein 33% ofparticles have a diameter of less than 2 μm—in a 20-L stainless steelreactor, such that the aqueous suspension obtained has a solids contentcorresponding to 16 wt % by dry weight relative to the total suspensionweight. The temperature of this suspension is thereafter is brought toand maintained at 70° C.

Under stirring at approximately 1000 rpm such that an essential laminarflow is established phosphoric acid in the form of a 30% solution isadded to the calcium carbonate suspension through a separate funnel overa period of 10 minutes in an amount corresponding to 30% by weight ondry calcium carbonate weight. Following this addition, the suspension isstirred for an additional 5 minutes.

The resulting suspension was allowed to settle overnight, and the FCChad a specific surface area of 46 m²/g, and d₅₀ of 9.5 μm (Malvern) andd₉₈ of 18.9 (Malvern).

Starting Material: Marble

A calcium carbonate suspension is prepared by adding water andundispersed marble of (ground under wet conditions in water, optionallyin the presence of a food approved dispersing or grinding aid such asMonopropyleneglycol (MPG)) having a d₅₀ of 2 μm, wherein 48% ofparticles have a diameter of less than 2 μm—in a 20-L stainless steelreactor, such that the aqueous suspension obtained has a solids contentcorresponding to 16 wt % by dry weight relative to the total suspensionweight. The temperature of this suspension is thereafter is brought toand maintained at 70° C.

Under stirring at approximately 1000 rpm such that an essential laminarflow is established phosphoric acid in the form of a 30% solution isadded to the calcium carbonate suspension through a separate funnel overa period of 10 minutes in an amount corresponding to 50% by weight ondry calcium carbonate weight. Following this addition, the suspension isstirred for an additional 5 minutes.

The resulting suspension was allowed to settle overnight, and the FCChad a specific surface area of 71 m²/g, and d₅₀ of 10.6 μm (Malvern) andd₉₈ of 21.8 (Malvern).

Similarly, functionalized precipitated calcium carbonate is obtained. Ascan be taken in detail from EP 2 070 991 B1 from the same applicant,wherein functionalized precipitated calcium carbonate is obtained bycontacting precipitated calcium carbonate with H₃O⁺ ions and with anionsbeing solubilized in an aqueous medium and being capable of formingwater-insoluble calcium salts, in an aqueous medium to form a slurry offunctionalized precipitated calcium carbonate, wherein saidfunctionalized precipitated calcium carbonate comprises an insoluble, atleast partially crystalline calcium salt of said anion formed on thesurface of at least part of the precipitated calcium carbonate.

Said solubilized calcium ions correspond to an excess of solubilizedcalcium ions relative to the solubilized calcium ions naturallygenerated on dissolution of precipitated calcium carbonate by H₃O⁺ ions,where said H₃O⁺ ions are provided solely in the form of a counter ion tothe anion, i.e. via the addition of the anion in the form of an acid ornon-calcium acid salt, and in absence of any further calcium ion orcalcium ion generating source.

Said excess solubilized calcium ions are preferably provided by theaddition of a soluble neutral or acid calcium salt, or by the additionof an acid or a neutral or acid non-calcium salt which generates asoluble neutral or acid calcium salt in situ.

Said H₃O⁺ ions may be provided by the addition of an acid or an acidsalt of said anion, or the addition of an acid or an acid salt whichsimultaneously serves to provide all or part of said excess solubilizedcalcium ions.

In a preferred embodiment of the preparation of the functionalizednatural or synthetic calcium carbonate, the natural or synthetic calciumcarbonate is reacted with the acid and/or the carbon dioxide in thepresence of at least one compound selected from the group consisting ofaluminium sulfates, silicate, silica, aluminium hydroxide, earth alkalialuminate such as sodium or potassium aluminate, magnesium oxide, ormixtures thereof. Preferably, the at least one silicate is selected froman aluminium silicate, a calcium silicate, or an earth alkali metalsilicate. These components can be added to an aqueous suspensioncomprising the natural or synthetic calcium carbonate before adding theacid and/or carbon dioxide.

Alternatively, the silicate and/or silica and/or aluminium hydroxideand/or earth alkali aluminate and/or magnesium oxide component(s) can beadded to the aqueous suspension of natural or synthetic calciumcarbonate while the reaction of natural or synthetic calcium carbonatewith an acid and carbon dioxide has already started. Further detailsabout the preparation of the functionalized natural or synthetic calciumcarbonate in the presence of at least one silicate and/or silica and/oraluminium hydroxide and/or earth alkali aluminate component(s) aredisclosed in WO 2004/083316, the content of this reference herewithbeing included in the present application.

The functionalized natural or synthetic calcium carbonate can be kept insuspension, optionally further stabilised by a dispersant. Conventionaldispersants known to the skilled person can be used. A preferreddispersant is polyacrylic acid or partially or totally neutralizedpolyacrylic acid.

Alternatively, the aqueous suspension described above can be dried,thereby obtaining the solid (i.e. dry or containing as little water thatit is not in a fluid form) functionalized natural or synthetic calciumcarbonate in the form of granules or a powder.

In a preferred embodiment, the functionalized natural or syntheticcalcium carbonate has a BET specific surface area of from 5 m²/g to 200m²/g, preferably 20 m²/g to 150 m²/g, more preferably 40 m²/g to 100m²/g, measured using nitrogen and the BET method according to ISO9277:2010.

Furthermore, it is preferred that the functionalized natural orsynthetic calcium carbonate has a weight median grain diameter of from0.1 to 50 μm, preferably from 0.5 to 25 μm, more preferably from 0.8 to20 μm, still more preferably from 1 to 15 μm, measured using MalvernMastersizer X long bed.

In a preferred embodiment, the functionalized natural or syntheticcalcium carbonate (FCC) has a BET specific surface area within the rangeof 5 m²/g to 200 m²/g and a weight median grain diameter within therange of 0.1 m to 50 μm. More preferably, the specific surface area iswithin the range of 20 m²/g to 150 m²/g and the weight median graindiameter is within the range of 0.5 m to 25 μm. Even more preferably,the specific surface area is within the range of 40 m²/g to 100 m²/g andthe weight median grain diameter is within the range of 1 μm to 15 μm.

By the above described process natural or synthetic calcium carbonate ismodified to enhance on one hand the porosity of the FCC and on the otherhand to enlarge the surface area. The FCC absorbs water at a faster ratecompared to conventional calcium carbonate and is able to absorb tentimes more fluid than conventional calcium carbonate. Reference is madeto C. J. Ridgway et al. “Modified calcium carbonate coatings with rapidabsorption and extensive liquid uptake capacity”, Colloids and SurfacesA: Physicochemical and Engineering Aspects, vol. 236, no. 1-3, pp.91-102, April 2004.

In this respect, it is believed that because of the intra and interporestructure of the functionalized calcium carbonate, air is entrapped inthe pores which promotes flotation of the particles.

Preferably, the functionalized natural or synthetic calcium carbonatehas an intra-particle porosity within the range from 20 vol.-% to 99vol.-%, preferably from 30 vol.-% to 70 vol.-%, more preferably from 40vol.-% to 60 vol.-% calculated from a mercury porosimetry measurement.From the bimodal derivative pore size distribution curve the lowestpoint between the peaks indicates the diameter where the intra andinter-particle pore volumes can be separated. The pore volume atdiameters greater than this diameter is the pore volume associated withthe inter-particle pores. The total pore volume minus this interparticle pore volume gives the intra particle pore volume from which theintra particle porosity can be calculated, preferably as a fraction ofthe solid material volume, as described in Transport in Porous Media(2006) 63: 239-259.

Thus, the intra-particle porosity determined as the pore volume per unitparticle volume is within the range of from 20 vol.-% to 99 vol.-%,preferably from 30 vol.-% to 80 vol.-%, more preferably from 40 vol.-%to 70 vol.-%, most preferably from 50 vol. % to 65 vol. %.

Due to the high porosity of the functionalized natural or syntheticcalcium carbonate, on one side a significant amount of air is present inthe pores, which upon contact with the gastric fluid is displaced andwater as well as gastric fluid enter the pores and may start anuncontrolled decomposition of the functionalized natural or syntheticcalcium carbonate thereby releasing CO₂. In order to preventuncontrolled dissolution and the water and/or gastric fluid entering thepores, the functionalized natural or synthetic calcium carbonate ismixed with at least one formulating aid. Said formulating aid being atleast one film forming compound and/or composition. Said compound and/orcomposition can be selected from hydrophilic film forming excipients orfrom lipophilic film forming excipients and combinations thereof, andare present in amount from about 1 wt % to about 60 wt %, preferablyfrom about 3 wt % to about 60 wt %, more preferably from about 5 wt % toabout 60 wt % based in the total weight of the formulation.

Hydrophilic film forming excipients resulting in hydrophilicformulations comprise but are not limited to water soluble polyethyleneglycols, polyethylene oxides, polypropylene glycols, polypropyleneoxides or combinations thereof, said polymers having a weight averagemolecular weight from 2,000 Da to 20,000,000 Da, Chitosan, Polymers ofacrylic acid, Polyvinylpyrrolidon and its modifications (insolublecross-linked polyvinylpyrollidones, homopolymers ofN-vinyl-2-pyrrolidone), modified cellulose gums, starch glycolates,pregelatinized starch, sodium carboxymethyl starch, low-substitutedhydroxypropyl cellulose, alkyl-, hydroxyalkyl-, carboxyalkyl-celluloseesters, hydroxpropyl methyl cellulose phthalate, carboxymethylcellulosesalts, alginates, ion exchange resins, gums, chitin, clays, gellan gum,crosslinked polacrillin copolymers, agar, gelatin, dextrines, shellacand combinations thereof.

Lipophilic film forming excipients resulting in lipophilic formulationscomprise but are not limited to hydrogenated vegetable, castor oils,mineral oils, waxes fatty acids and fatty acid salts with a carbon chainlengths from C₆ to C₂₀, being branched, un-branched, unsaturated,partially saturated, and their combinations, magnesium and/or calciumstearate, paraffin, cetyl alcohol, cetyl stearyl alcohol, glycerilmonostearate, lanolin, lanolin alcohols, polyethylene glycol ethers ofn-alkanols, polyoxyethylene castor oil derivates, polyoxyethylenesorbitan fatty acid esters, polyethylene stearates, sorbitan esters,stearyl alcohol, glycerol dibehenate, sodium stearyl fumarate, glyceroldistearate and combinations thereof.

The instantly floating gastroretentive formulation of the presentinvention may optionally further comprise at least one water solubleacid. Said water soluble acid is preferably selected from acids in solidfrom such as citric acid, fumaric acid, tartaric acid, or malic acid andcombinations thereof. Such acid or their combinations being present inamounts of up to 10 wt %, preferably up to 8 wt %, still more preferablyup to 5 wt %, based on the total weight of the formulation.

The formulation thus obtained is submitted to a compaction process,wherein the functionalized natural or synthetic calcium carbonate, theat least one pharmaceutically active ingredient or inactive precursor,formulation aids, and the optional water soluble acid, are made intogranules. The granulation process can be selected from melt, dry or wetgranulation process as well as roller compaction, extrusionspheronisation or hot melt extrusion. Due to the water susceptibility ofthe acid, wet granulation is preferably carried out using a non-waterbased granulation liquid. Such non-water based granulation liquid is forexample ethanol 96%.

The granules obtained by any of the previously described granulationprocess, are instantly floating gastrorententive granules. Such granulescan be dosed directly when packaged into sachets or stick packs. Thegranules can also be compacted into tablets or mini-tablets, or pellets.A further dosage form is in the form of capsules.

The inventors believe, without being bound by any theory, that thegranules comprising the functionalized natural or synthetic calciumcarbonate, mixed with a film forming agent and optionally said solidwater soluble acid, the pores are covered or at least partially covered,closed or partially closed thereby trapping air inside the pore, therebyenhancing the floatability of the granules.

The optional addition of the water soluble acid is intended to providean H+ donor when contacted with the gastric fluid. This H+ donor isbelieved to support the floating properties in the following way. Thefunctionalized natural or synthetic calcium carbonate wherein the poresare partially or completely closed comprises air in the closed orpartially closed pores.

Upon contact with the gastric fluid partial erosion of thefunctionalized natural or synthetic calcium carbonate takes place andpart of the entrapped air plug may be liberated. However, due to theadditional H+ donor, portions of the functionalized natural or syntheticcalcium carbonate decompose further thereby liberating CO₂ whichpartially replaces the liberated air form the air plug. By thisflotation is supported even with ongoing erosion of the granules.

When the granules are compacted to tablets this effect is slowed down,due to the smaller surface being accessible by the gastric fluid. As thefilm forming compounds and/or compositions partially protect the poresform excessive erosion from the gastric fluid and/or water, the tableswill sufficiently long persist in the stomach floating on the gastricfluid. Even if the pores on the surface are eroded and filled withfluid, the buoyancy is still preserved due to the film forming compoundsand/or compositions protecting the underlying pored form beingprematurely eroded.

In a particular embodiment the instantly floating gastroretentiveformulation is in the form of a tablet. Said tablet further comprisingadditional compounds such as fillers, binders, diluents, adhesives,lubricants or miscellaneous materials such as buffers and adsorbents,natural or synthetic scenting agents, natural or synthetic flavoringagents, natural or synthetic coloring agents, natural or syntheticsweeteners and/or mixtures thereof.

Suitable natural or synthetic scenting agents include one or morevolatilized chemical compounds, generally at a very low concentration,that humans or other animals perceive by the sense of olfaction.

Suitable natural or synthetic flavoring agents include but are notlimited to mints, such as peppermint, menthol, vanilla, cinnamon,various fruit flavors, both individual or mixed, essential oils such asthymol, eucalyptol, menthol, and methyl salicylate, allylpyrazine,methoxypyrazines, 2-isobutyl-3 methoxypyrazine, acetyl-L-pyrazines,2-acetoxy pyrazine, aldehydes, alcohols, esters, ketones, pyrazines,phenolics, terpenoids and mixtures thereof.

The flavoring agents are generally utilized in amounts that will varydepending upon the individual flavor, and may, for example, range inamount of about 0.5% to about 4% by weight of the final composition.

Suitable natural or synthetic coloring agents include, but are notlimited to, titanium dioxide, flavone dyes, iso-quinoline dyes, polyenecolorants, pyran colorants, naphthochinone dyes, chinone andanthrachinone dyes, chromene dyes, benzophyrone dyes as well as indigoiddyes and indole colorants. Examples thereof are caramel coloring,annatto, chlorophyllin, cochineal, betanin, turmeric, saffron, paprika,lycopene, pandan and butterfly pea.

Suitable natural or synthetic sweeteners include but are not limited toxylose, ribose, glucose, mannose, galactose, fructose, dextrose,sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrupsolid, and sugar alcohols such as sorbitol, xylitol, mannitol, andmixtures thereof, water soluble artificial sweeteners such as thesoluble saccharin salts, i.e. sodium, or calcium saccharin salts,cyclamate salts, acesulfam-K and the like, and the free acid form ofsaccharin and aspartame based sweeteners such asL-aspartyl-phenylalanine methyl ester, Alitame® or Neotame®.

In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular tablet composition.

Within the context of the present invention, a pharmaceutically activeingredient refers to pharmaceutically active ingredients which are ofsynthetic-, semi-synthetic or of natural origin or combinations thereof.Such active ingredient encompasses also inactive pharmaceutical andbiological precursors which will be activated at a later stage.

The activation of such inactive precursors is known to the skilledperson and commonly in use, e.g. activation in the stomach and/orgastro-intestinal pathway-such as acidic activation or tryptic- orchimotryptic cleavage.

It lies within the understanding of the skilled person that thementioned activation methods are of mere illustrative character and arenot intended to be of limiting character.

The present invention refers also to a process or a method for producingan instantly floating gastroretentive formulation comprising the steps:

-   -   a) providing a functionalized natural and/or synthetic calcium        carbonate comprising mineral, wherein said functionalized        natural or synthetic calcium carbonate is a reaction product of        natural or synthetic calcium carbonate with carbon dioxide and        one or more acids, wherein the carbon dioxide is formed in situ        by the acid treatment and/or is supplied from an external        source;    -   b) providing at least one pharmaceutically active ingredient;    -   c) providing at least one formulating aid;    -   d) mixing the compounds provided in steps a) b) and c)    -   e) granulating the mixture of step d)

The granulation of the instantly floating gastroretentive formulationcan also be performed by roller compaction.

In the method of the present invention the source of natural calciumcarbonate for preparing the functionalized calcium carbonate (FCC) isselected from the group of marble, calcite, chalk, limestone anddolomite and/or mixtures thereof.

In a particular embodiment the synthetic calcium carbonate for preparingthe functionalized calcium carbonate is precipitated calcium carbonate(PCC) comprising aragonitic, vateritic or calcitic mineralogicalcrystals forms, especially prismatic, rhombohedral or scalenohedral PCCor mixtures thereof.

The functionalized natural or synthetic calcium carbonate used in themethod of the present invention has a BET specific surface area of from5 m²/g to 200 m²/g, preferably 20 m²/g to 150 m²/g, more preferably 40m²/g to 100 m²/g, measured using nitrogen and the BET method accordingto ISO 9277:2010.

Furthermore, it is preferred that the functionalized natural orsynthetic calcium carbonate in method of the present invention has aweight median grain diameter of from 0.1 to 50 μm, preferably from 0.5to 25 μm, more preferably from 0.8 to 20 μm, still more preferably from1 to 15 μm, measured using Malvern Mastersizer X long bed.

In the method of the present invention the at least one pharmaceuticallyactive ingredient or inactive precursor is selected from synthetic-,semi-synthetic or natural origin or combinations, thereof.

The activation of such inactive precursors is known to the skilledperson and commonly in use, e.g. activation in the stomach and/orgastro-intestinal pathway-such as acidic activation, alkalineactivation, tryptic-, chimotryptic or pepsinogenic activation byenzymatic cleavage.

The method of the present invention may be also varied in that parts ofthe formulation aid of step c) is first mixed with the FCC of step a)and the at least one pharmaceutically active ingredient of step b), andthe remaining portion of the formulation aid is then added to themixture, followed by the granulation step e).

In the method of the present invention, the at least one formulating aidis at least one film forming compound and/or composition.

Said compound and/or composition can be selected from hydrophilic filmforming excipients or from lipophilic film forming excipients andcombinations thereof, and are present in amount from about 1 wt % toabout 60 wt %, preferably from about 3 wt % to about 60 wt %, morepreferably from about 5 wt % to about 60 wt % based in the total weightof the formulation.

Hydrophilic film forming excipients resulting in hydrophilicformulations comprise but are not limited to water soluble polyethyleneglycols, polyethylene oxides, polypropylene glycols, polypropyleneoxides or combinations thereof, said polymers having a weight averagemolecular weight from 2,000 Da to 20,000,000 Da, Chitosan, Polymers ofacrylic acid, Polyvinylpyrrolidon and its modifications (insolublecross-linked polyvinylpyrollidones, homopolymers ofN-vinyl-2-pyrrolidone), modified cellulose gums, starch glycolates,pregelatinized starch, sodium carboxymethyl starch, low-substitutedhydroxypropyl cellulose, alkyl-, hydroxyalkyl-, carboxyalkyl-celluloseesters, hydroxpropyl methyl cellulose phthalate, carboxymethylcellulosesalts, alginates, ion exchange resins, gums, chitin, clays, gellan gum,crosslinked polacrillin copolymers, agar, gelatin, dextrines, shellacand combinations thereof.

Lipophilic film forming excipients resulting in lipophilic formulationscomprise but are not limited to hydrogenated vegetable, castor oils,mineral oils, waxes fatty acids and fatty acid salts with a carbon chainlengths from C₆ to C₂₀, being branched, un-branched, unsaturated,partially saturated, and their combinations, magnesium and/or calciumstearate, paraffin, cetyl alcohol, cetyl stearyl alcohol, glycerilmonostearate, lanolin, lanolin alcohols, polyethylene glycol ethers ofn-alkanols, polyoxyethylene castor oil derivates, polyoxyethylenesorbitan fatty acid esters, polyethylene stearates, sorbitan esters,stearyl alcohol, glycerol dibehenate, sodium stearyl fumarate, glyceroldistearate and combinations thereof.

In the method of the present invention a water soluble acid can be addedin either of the steps a), b) or c), i.e. the water soluble acid isadded prior to step d). In a particular method the water soluble acidcan be added in portions in either of the step a), b) and/or c).

The acid is present in amounts of up to 10 wt %, preferably up to 8 wt%, still more preferably up to 5 wt %, based on the total weight of theformulation.

The water soluble acid is preferably selected from acids in solid fromsuch as citric acid, fumaric acid, tartaric acid, or malic acid andcombinations thereof.

The present in invention refers also to the use of functionalizednatural or synthetic calcium carbonate comprising mineral in instantfloating gastroretentive formulations. Such formulations being made intodosage forms comprising tablets, mini-tablets, granules, capsules orpellets.

The present invention further refers to the use of functionalizednatural or synthetic calcium carbonate comprising mineral in the processor method for preparing instant floating gastroretentive formulations.Such formulations being made into dosage forms comprising tablets,mini-tablets, granules, capsules or pellets.

The present invention further refers to the use of functionalizednatural or synthetic calcium carbonate in instantly floatinggastroretentive formulations as previously described.

The present invention further refers also to the use of functionalizednatural or synthetic calcium carbonate for preparing an instantlyfloating gastroretentive formulation.

The present invention still further refers to tablets, mini-tablets,granules, capsules or pellets, comprising the instantly floatinggastroretentive formulations of the present invention.

The present invention still further refers tablets, mini-tablets,granules, capsules or pellets, comprising the instantly floatinggastroretentive formulation, wherein said formulation is obtained by theherein described methods.

The present invention is now further explained by way of the followingfigures and examples, which are only illustrative and are not intendedto restrict the invention in any way.

DESCRIPTION OF THE FIGURES

FIG. 1a is a schematic representation of the proposed stomach modelmethod to evaluate floating behavior and drug release

FIG. 1b is a schematic representation of a single unit of FIG. 1 a.

FIG. 2 shows caffeine release profiles of small-sized and standard-sizedtablets of floating formulation HF1 and LF2.

FIG. 3 shows a comparison of caffeine release profiles of standard-sizedfloating tablets tested using stomach model and USP dissolutionapparatus II.

EXAMPLES Preparation of FCC-Based Floating Formulations

The instantly floating gastroretentive formulation of the presentinvention were prepared according to table 1.

For a hydrophilic formulation (HF1), the required amount of FCC, a watersoluble polyethylene oxide (Polyox™ WSR 301, form The Dow ChemicalCompany, USA), a low substituted hydroxypropyl methyl cellulose(Methocel® K 100 Premium LV from Sandoz Pharma AG, Switzerland) andcitric acid (Acid citricum monohydr. pulvis, Hänsler AG, Switzerland)and as a model drug caffeine (Coffeiunm WSF, from Bohringer-Ingelheim,Germany) were weighted and mixed in a tumbling mixer (Turbula, type T2C,Switzerland) at room temperature, for 10 min at 33 rpm. Afterwards,ethanol (96%) was added as granulation liquid. The granulation processwas carried out by slurryfication in a beaker. Ethanol was added untilthe mass was turning into stable, homogeneous slurry. The obtainedslurry was dried and passed through a sieve (1000 μm).

For a lipophilic formulation (LF2), the required amount of FCC, a watersoluble polyethylene oxide (Polyox™ WSR 301, form The Dow ChemicalCompany, USA), hydrogenated vegetable oil (Lubritab®, JRS Pharam,Germany), and caffeine as model drug where weighted. Prior to its use,Lubritab® was melted. FCC, caffeine and half of the melted Lubritab® wasadded under stirring conditions. Afterwards, Polyox™ WSR 301 and theremaining half of Lubritab® were added under stirring with magneticstirrer. Upon cooling the stirred mass the granules were obtained due toin-situ agglomeration.

The obtained granules were passed through a sieve (1000 m).

TABLE 1 Composition of floating compositions. Methocel ® K100 CitricCaf- FCC Polyox ™ Premium acid feine Formu- (%, WSR 301 LV (%,Lubritab ® (%, lation w/w) (%, w/w) (%, w/w) w/w) (%, w/w) w/w) HF156.25 7.50 10.875 0.375 — 25.00 LF2 37.50 5.00 — — 40.83 16.67

Preparation of Tablet Comprising the FCC-Based Floating Formulation

Instantly floating gastroretentive tablets were prepared by compactingthe FCC-based floating formulation HF1 and LF2 using a single puncheccentric press (Korsch EKO, Germany) according to table 2. Resultingtablet heights were calculated to yield densities of 0.8 g/cm3 and 0.9g/cm3 for the hydrophilic and lipophilic formulations respectively. Thepunch gap for compaction process was set to calculated values for HF andLF formulations respectively. Two sizes of tablets were manufactured:standard-sized and small-sized. The small-sized compacts were used as amodel for mini-tablets (i.e. tablets with diameter less than 3 mm¹).Standard-sized tablets were flat-faced, whereas the small-sized tabletshad a concave shape.

TABLE 2 Preparation of floating tablets. Standard-sized tabletsSmall-sized tablets Formu- amount radius height amount radius Heightlation (mg) (mm) (mm) (mg) (mm) (mm) HF1 400 5.50 5.00 50 2.5 3.83 LF2600 5.50 7.00 75 2.5 4.54The tablets were further characterized and the results are summarized intable 3.

TABEL 3 Properties of produced floating tablets. true density diam-thick- tensile poros- of floating weight eter ness strength ity mixtureFormulation mg mm mm N/mm² % g/cm³ HF1 400 11.01 4.98 0.67 59 2.0101standard HF1 small s. 50 5.00 3.83 1.06 60 2.0101 LF2 standard 600 11.016.98 0.17 37 1.4359 LF2 small s. 75 5.00 4.56 0.47 32 1.4359

Evaluation of In Vitro Floating Behavior and Drug Release

To simultaneously assess in vitro floating characteristics and drugrelease of tablets (n=4), a—dissolution apparatus (Sotax AT7smart,Switzerland) modified according to schematics in FIG. 1 (i.e. 4 vesselswere exchanged with Erlenmeyer 500 ml flasks) was used wherein theexperimental setup (FIG. 1) consisted of 4 polycarbonate Erlenmeyerflasks (500 ml) which were fixed on the carriage of a water bath shaker(Kobrin Scientific precision centigrade temperature processor 345,Switzerland). The carriage moved horizontally with rotation speed of 75rpm and amplitude of 50 mm. Measurement was performed using 400 ml 0.1 NHCl as test media at a temperature of 37° C.

For comparison, floating behavior and drug release (n=3) were analyzedusing USP dissolution apparatus II (Sotax AT 7 smart, Switzerland).Measurement was done in 900 ml 0.1 N HCl with paddle rotation of 100 rpmand at temperature of 37±0.5° C.

Drug content was analyzed in the dissolution media at predetermined timeintervals using UV/Vis spectrophotometer at 272 nm (Perkin Elmer Lambda25, USA). The UV absorption spectrum of caffeine exhibits a pair ofabsorption bands peaking at 205 nm and 273 nm with a characteristicabsorption shoulder between them.

Typically, caffeine content is determined by measuring the absorbancenear the 273 nm peak.

Floating lag time of reference is defined as time a tablet needed torise to the surface of the test medium after placing it into the testmedium and floating duration noted as total time a tablet constantlyfloated on the surface of the test medium were visually observed.

Caffeine release profiles of floating tablets of hydrophilic andlipophilic formulation are displayed in FIG. 2. Standard-sized tabletsof both formulations showed instant flotation. In case of formulationHF1, compacts were floating for 5 h and eroded completely within thistime while releasing drug substance and stay afloat. For lipophilicformulation LF2, it was observed that floating times were of severaldays. After complete release of model drug, a lipophilic matrixremained. Drug release mechanism of the two types of floatingformulations differs: erosion-controlled for formulation HF1 anddiffusion-controlled for hydrophobic formulation LF2. For hydrophilicfloating tablets, all of the caffeine was released after 5 h, while forlipophilic formulations complete drug release was detected after 59 h 45min.

FIG. 2 further illustrates drug release profiles of small-sized floatingtablets of formulation HF1 and LF2. No floating lag times were observedfor both formulations. For compacts of hydrophilic formulation HF1,floating times of 90 min were measured and tablets dissolved completely.Drug release mechanism was classified as erosion-controlled; after 90min 100% caffeine release was achieved. Small-sized tablets offormulation LF2 were floating for several days and a lipophilic tabletmatrix was retained. Drug release was diffusion-controlled; after 17 hdrug substance was completely released. Release profile (FIG. 2) offormulation LF2 shows disintegration of small-sized floating tablets at210 min.

Comparison of Stomach Model and USP Dissolution Apparatus II

FIG. 3 compares the drug release of floating tablets measured using thecustom-built stomach model (schematic of stomach model apparatus isshown in FIG. 1) with the conventional USP dissolution apparatus II.Dissolution testing by USP paddle method resulted in a slowdown ofcaffeine release; 100% drug substance was released after 470 min. Duringmeasurement the FCC-based tablets were floating on test media surfaceand rotating around the paddle shaft. Using the stomach model method,complete caffeine release of standard-sized tablets of formulation HF1was assessed after 300 min. Due to horizontal movement of the shaker,floating tablets were fully immersed in the dissolution media and dryingof the tablet surface was avoided.

In Vitro Drug Release of FCC-Based Floating Tablets

In vitro testing of FCC-based tablets showed that manufacturing offloating tablets with different release profiles is possible.Small-sized tablets were releasing drug faster. This could be explainedby their higher surface area. It was further observed that the sizeeffect was independent of the formulation type (i.e. lipophilic orhydrophilic). In case of hydrophilic tablet formulation disintegrationdid not happen; this supports the hypothesis of erosion-controlled drugrelease mechanism. Small-sized lipophilic tablets disintegrated at 210min. The alteration of the release profile is supporting the hypothesisof diffusion-controlled release mechanism from lipophilic formulations.

FCC for the Preparation of Floating Tablets

FCC seems to be a promising new pharmaceutical excipient for preparationof floating tablets. Due to its highly porous structure and lamellarsurface it is possible to manufacture compacts which have a density lessthan unity and are instantly floating. The prepared floating tabletsexhibited no floating lag time and hence a reduced risk forunpredictable and premature gastric emptying. Furthermore, FCC-basedfloating tablets showed a sufficient hardness to resist destruction bygastric peristalsis and to be further processible.

Two floating formulations—hydrophilic and hydrophobic—were prepared.According to results of preliminary trials, a granulation step seemed tobe necessary for production of FCC-based floating formulations toimprove flowability and fillability of the mixtures into the die of thetablet press.

Caffeine release profiles showed that lipophilicity of the formulationinfluenced drug release rate as well as drug release mechanism. Tabletsize affected drug release rate, but did not have an influence onrelease mechanism.

Custom-Built Stomach Model

Stomach model showed good performance to overcome the limitations of thestandard methods. The floating tablets were not drying on the surfacedue to continuous shaking of the dissolution vessels. Absence ofrotating elements excluded the effects observed in USP dissolutionapparatus I and II. In addition, there was no need to force the tabletsunder the liquid surface, hence simplifying the construction of thestomach model. During the test the dissolution media was protecting thetablets from significant impacts with solid construction elements.

In comparison to traditional in vitro dissolution testing by USPapparatus I or II, the proposed stomach model offers the possibility toinvestigate drug release of floating delivery devices with taking intoaccount gastric motility. Therefore the conclusion is that the newmethod might be able to predict with higher accuracy in vivo behavior offloating tablets.

Measurement Methods True Density

The true density of FCC was determined by helium pycnometry(Micromeritics AccuPyc 1330, USA).

BET Specific Surface Area

To measure the specific surface area, a Nova 2000e (QuantachromeInstruments, USA) was used with the five point BET method. Afterdegassing the samples for 12 hours at room temperature, the samples weremeasured with nitrogen at constant temperature (77.4 K). The measurementwas performed in duplicate.

Particle Size Distribution

Particle size distribution was determined with a Mastersizer X long bed(Malvern Instruments, UK). FCC particles were dispersed in isopropylmyristate and then analyzed (separately) by using the small volumesample presentation unit (Malvern Instruments, UK). The samples weremeasured in triplicate.

Characterization of FCC-Based Floating Tablets

Mean tablet weight (n=7) was measured with an electronic balance(Mettler Toledo AX204 Delta Range, Switzerland). Determination of tabletdiameter (n=7) and tablet thickness (n=7) was done using a dialindicator (Mitutoyo Model CD-15CPX, Japan). Helium pycnometry(Micromeritics AccuPyc 1330, USA) was performed to measure true density.The porosity c of flat-faced tablets was calculated according to thefollowing equation (1):

$\begin{matrix}{ɛ = {\left( {1 - \frac{\frac{m}{\rho}}{\pi \cdot r^{2} \cdot h}} \right) \cdot 100}} & (1)\end{matrix}$

wherein m is the tablet weight, p is the true density of the powdermixture, r is the tablet radius, and h is the tablet height. Porosity cof concave-shaped compacts was calculated as follows:

$\begin{matrix}{ɛ = {\left( {1 - \frac{\frac{m}{\rho}}{{\pi \cdot r^{2} \cdot w} + {2\left( {\frac{\pi \cdot h_{cap}}{6} \cdot \left( {{3\; r^{2}} + h_{cap}^{2}} \right)} \right.}}} \right) \cdot 100}} & (2)\end{matrix}$

wherein m is the tablet weight, p is the true density of the powdermixture, r is the tablet radius, w is the central cylinder thickness,and h_(cap) is the height of the spherical cap.

A hardness tester (Tablet Tester 8M, Switzerland) was used to analyzetablet breaking strength (n=3). Afterwards, tablet tensile strength, a(MPa) was calculated according to equation 3 and 4 for flat-faced andconcave-shaped tablets, respectively.

$\begin{matrix}{\sigma_{t} = \frac{2 \cdot F}{\pi \cdot d \cdot h}} & (3)\end{matrix}$

wherein F is the diametrical crushing force, d is the tablet diameter,and h is the tablet height.

$\begin{matrix}{\sigma_{t} = {\frac{10 \cdot F}{\pi \cdot d^{2}} \cdot \left( {{2.84 \cdot \frac{h}{d}} - {0.126 \cdot \frac{h}{w}} + {3.15 \cdot \frac{w}{d}} + 0.01} \right)^{- 1}}} & (4)\end{matrix}$

wherein F is the diametrical crushing force, d is the tablet diameter, his the tablet height, and w is the central cylinder thickness.

UV/VIS Measurements

Drug content was analyzed online in the dissolution media atpredetermined time intervals using UV/Vis spectrophotometer at 272 nm(Perkin Elmer Lambda 25, USA). The UV absorption spectrum of caffeineexhibits a pair of absorption bands peaking at 205 nm and 273 nm with acharacteristic absorption shoulder between them. Typically, caffeinecontent is determined by measuring the absorbance near the 273 nm peak.

1. A method for producing an instantly floating gastroretentive formulation comprising the steps: a) providing a functionalized natural or synthetic calcium carbonate comprising mineral (FCC), wherein the functionalized natural or synthetic calcium carbonate is a reaction product of natural or synthetic calcium carbonate with carbon dioxide and one or more acids, wherein the carbon dioxide is formed in situ by the acid treatment and/or is supplied from an external source; b) providing at least one pharmaceutically active ingredient; c) providing at least one formulating aid; d) mixing the compounds provided in steps a), b) and c); and e) granulating the mixture obtained in step d) by way of melt, dry or wet granulation or roller compaction.
 2. The method according to claim 1, wherein a part of the formulation aid of step c) is first mixed with the functionalized calcium carbonate (FCC) of step a) and the at least one pharmaceutically active ingredient of step b), and the remaining portion of the formulation aid is then added to the mixture, followed by the granulation step e).
 3. The method according to claim 1, wherein the functionalized calcium carbonate (FCC) is prepared from natural calcium carbonate selected from the group consisting of marble, calcite, chalk, limestone, dolomite, and any mixture thereof.
 4. The method according to claim 1, wherein the functionalized calcium carbonate (FCC) is prepared from synthetic calcium carbonate that is precipitated calcium carbonate (PCC) having one or more aragonitic, vateritic, prismatic, rhombohedral or scalenohedral forms.
 5. The method according to claim 1, wherein the one or more acids is selected from the group consisting of hydrochloric acid, sulfuric acid, sulfurous acid, hydrosulfate, phosphoric acid, phosphoric acid in combination with acetic, formic or citric acid or acid salts thereof, and any mixture thereof.
 6. The method according to claim 1, wherein the one or more acids is phosphoric acid.
 7. The method according to claim 1, wherein the functionalized natural or synthetic calcium carbonate has a BET specific surface area of from 5 m²/g to 200 m²/g, measured using nitrogen and the BET method according to ISO 9277:2010.
 8. The method according to claim 1, wherein the functionalized natural or synthetic calcium carbonate has a BET specific surface area of from 20 m²/g to 150 m²/g, measured using nitrogen and the BET method according to ISO 9277:2010.
 9. The method according to claim 1, wherein the functionalized natural or synthetic calcium carbonate has a BET specific surface area of from 40 m²/g to 100 m²/g, measured using nitrogen and the BET method according to ISO 9277:2010.
 10. The method according to claim 1, wherein the functionalized natural or synthetic calcium carbonate has a weight median grain diameter of from 0.1 to 50 μm, measured using Malvern Mastersizer X long bed.
 11. The method according to claim 1, wherein the functionalized natural or synthetic calcium carbonate has a weight median grain diameter of from 0.5 to 25 μm, measured using Malvern Mastersizer X long bed.
 12. The method according to claim 1, wherein the functionalized natural or synthetic calcium carbonate has a weight median grain diameter of from 0.8 to 20 μm, measured using Malvern Mastersizer X long bed.
 13. The method according to claim 1, wherein the functionalized natural or synthetic calcium carbonate has a weight median grain diameter of from 1 to 15 μm, measured using Malvern Mastersizer X long bed.
 14. The method according to claim 1, wherein the least one pharmaceutically active ingredient is an active agent or an inactive precursor that is synthetic-, semi-synthetic or of natural origin or any combination thereof.
 15. The method according to claim 1, wherein the at least one formulating aid is a film forming compound and/or composition.
 16. The method according to claim 15, wherein the film forming compound and/or composition is selected from the group consisting of hydrophilic film forming excipients, lipophilic film forming excipients, or any combination thereof.
 17. The method according to claim 1, wherein the at least one formulating aid is a hydrophilic film forming excipient selected from group consisting of water soluble polyethylene glycols, polyethylene oxides, polypropylene glycols, polypropylene oxides or any combination thereof, polymers having a weight average molecular weight from 2,000 Da to 20,000,000 Da, chitosan, polymers of acrylic acid, polyvinylpyrrolidon, insoluble cross-linked polyvinylpyrollidones, homopolymers of N-vinyl-2-pyrrolidone, modified cellulose gums, starch glycolates, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, alkyl-, hydroxyalkyl-, carboxyalkyl-cellulose esters, hydroxpropyl methyl cellulose phthalate, carboxymethylcellulose salts, alginates, ion exchange resins, gums, chitin, clays, gellan gum, crosslinked polacrillin copolymers, agar, gelatin, dextrines, shellac, and any combination thereof.
 18. The method according to claim 1, wherein the at least one formulating aid is a lipophilic film forming excipient selected from the group consisting of hydrogenated vegetable, castor oils, mineral oils, waxes fatty acids and fatty acid salts with a carbon chain lengths from C6 to C20, being branched, un-branched, unsaturated, partially saturated, and any combination thereof, magnesium and/or calcium stearate, paraffin, cetyl alcohol, cetyl stearyl alcohol, glyceril monostearate, lanolin, lanolin alcohols, polyethylene glycol ethers of n-alkanols, polyoxyethylene castor oil derivates, polyoxyethylene sorbitan fatty acid esters, polyethylene stearates, sorbitan esters, stearyl alcohol, glycerol dibehenate, sodium stearyl fumarate, glycerol distearate, and any combination thereof.
 19. The method according to claim 16, wherein the film forming excipients are present in an amount from 1 wt % to 60 wt %, based in the total weight of the formulation.
 20. The method according to claim 1, wherein a water soluble acid is added prior to step d).
 21. The method according to claim 20, wherein the water soluble solid acid is selected from the group consisting of citric acid, fumaric acid, tartaric acid, malic acid, and any combination thereof.
 22. The method according to claim 20, wherein the acid is present in amounts of up to 10 wt %, based on the total weight of the formulation.
 23. The method according to claim 20, wherein the acid is present in amounts of up to 8 wt %, based on the total weight of the formulation.
 24. The method according to claim 20, wherein the acid is present in amounts of up to 5 wt %, based on the total weight of the formulation.
 25. The method according to claim 1, wherein the granulation step e) is followed by a compacting step f).
 26. The method according to claim 25, wherein the compacting step f) is pelletizing or tableting. 